Management of Right

Ven t r i c u l a r Fa i l u re i n
Pulmonary Embolism
a b,
Steven Zhao, MD , Oren Friedman, MD *

KEYWORDS
 Pulmonary embolism  Right ventricular failure  Cor pulmonale
 Massive pulmonary embolism  Extracorporeal membrane oxygenation (ECMO)
 Right ventricular support device (RVAD)

KEY POINTS
 Managing hemodynamic compromise from pulmonary embolism (PE) requires knowledge
of the pathophysiology of acute right ventricular failure.
 If patients are unstable, prioritize immediate clot reduction via systemic thrombolytics, en-
dovascular procedures, surgical embolectomy, or ECMO.
 Right ventricular failure from PE benefits from addition of systemic vasoconstrictors and
inotropes.
 Right ventricular assist devices may have a role in supporting right ventricular failure from
PE but more studies are needed.

INTRODUCTION

Significant hemodynamic compromise can be present in as many as 8% of patients

with an acute pulmonary embolism (PE). It is associated with a significant increase
in mortality from 15% to 42%, which is largely driven by acute right ventricular failure.1
Management of this complication is predicated on an understanding of the physiology
of the right ventricle (RV) in order to carefully support its cardiac output.

PATHOPHYSIOLOGY OF RIGHT VENTRICULAR FAILURE

The RV differs from the left ventricle (LV) in a few key areas. Pulmonary circulatory
pressures are markedly lower than those of its systemic counterpart. Accordingly,

a
Division of Pulmonary and Critical Care medicine, Cedars-Sinai Medical Center, 8700 Beverly
Boulevard, Room 6728, Los Angeles, CA 90048, USA; b Cedars-Sinai Medical Center, 127 South
San Vicente Boulevard, Los Angeles, CA 90048, USA
* Corresponding author.
E-mail address: oren.friedman@cshs.org
Twitter: @orenfriedman (O.F.)

Crit Care Clin 36 (2020) 505–515

https://doi.org/10.1016/j.ccc.2020.02.006 criticalcare.theclinics.com
0749-0704/20/ª 2020 Elsevier Inc. All rights reserved.
506 Zhao & Friedman

the RV consists of a thin layer of myofibrils arranged in series along the longitudinal
axis of the heart, which leads to a chamber that is well suited to accommodate
changes in volume but is poorly able to overcome sudden changes in pressure.2 In pa-
tients without preexisting pulmonary vascular disease, the RV is unable to acutely
generate pressures of more than 40 mm Hg during systole.3,4 RV stroke volume de-
creases precipitously as pulmonary vascular resistance (PVR) increases. First, the
RV dilates, and eventually contractility and output decrease. RV dilatation frequently
leads to functional tricuspid regurgitation as the tricuspid annulus enlarges. It is crucial
to remember that the pulmonary and systemic circulations are inexorably linked. A
decrease in RV cardiac output necessitates a decrease in LV cardiac output because
the LV cannot pump out any more blood than it receives. In addition, as the dilated RV
forces the interventricular septum to bow into the LV it impairs LV filling, a concept
known as interventricular dependence. LV filling is therefore reduced both in series
(reduced RV output leading to reduced LV filling) and in parallel (through interventric-
ular dependence). Perfusion of the RV occurs during both systole and diastole, and is
driven by the gradient between coronary artery pressures and RV transmural pres-
sures.5 As systemic pressure decreases and RV pressure increases, the RV can
become ischemic even in the absence of coronary disease. RV ischemia further
worsens RV cardiac output and feeds the cycle. Unless the cycle is broken, there is
a risk of progressive hemodynamic collapse.
An acute PE causes a sudden increase in RV afterload, both through direct in-
creases in PVR from clot burden as well as through neurohormonal and hypoxia-
mediated feedback mechanisms.6,7 This process is particularly exemplified by the
ability of PEs with low clot burden to still cause a significant increase in RV pres-
sures, and is likely mediated by molecules such as serotonin, thromboxane, and his-
tamine.8 This increase in PVR leads to an RV pressure and volume overload, which in
turn results in a decreased stroke volume. A compensatory neurohormonal cascade
increases chronotropy and inotropy, but, because the RV is unable to significantly
augment its stroke volume, the primary response to maintain cardiac output is tachy-
cardia. Dilatation of the RV free wall further impairs myocyte function as the chamber
moves past the inflection point on its Frank-Starling curve.5 Meanwhile, leftward
displacement of the interventricular septum impairs LV diastolic filling and reduces
LV stroke volume.9 As LV cardiac output decreases, systemic and therefore coro-
nary perfusing pressures decrease too. This reduced coronary perfusing gradient,
in combination with inflammatory changes and increased myocardial demand, pre-
cipitates RV ischemia. Thus, a feedback loop is generated wherein RV dysfunction
begets LV dysfunction, which in turn further injures the RV, forming the so-called
RV death spiral2,10–12 (Fig. 1).

PRELOAD OPTIMIZATION: VOLUME MANAGEMENT

Careful assessment of RV preload is exceedingly important because clinicians must

prevent the RV from being preload deficient and also avoid further stress on the
failing RV by worsening volume overload. There does not exist a reliable, well-
validated standard for predicting volume responsiveness in acute right ventricular
failure. Clinical judgment remains paramount, and every patient should be individu-
ally assessed.12 Guidance from studies is limited, as discussed later. This article first
explores several common intensive care unit (ICU) measurements used for fluid
management in other shock states. Static measurements such as central venous
pressure (CVP), although commonly used, have increasingly been shown to be un-
reliable as a marker of fluid responsiveness, especially in the setting of acutely
 Management of Right Ventricular Failure 507

Fig. 1. Physiology of right ventricular failure.

increased right-sided pressures and concomitant increases in tricuspid regurgita-

tion.13 Furthermore, it is impractical to place a central line for the sole purpose of
monitoring CVP in setting of acute PE, as patients will be on anticoagulation and
some are being considered for thrombolytics. However, the CVP is a good marker
of RV performance. If a patient already has existing central access, an increased
CVP usually implies fluid loading will be harmful. Dynamic measurements are gener-
ally considered superior to static measurements for predicting fluid responsiveness
in shock states; however, many dynamic measurements, such as pulse pressure
variation, stroke volume variation, and change in inferior vena cava with positive
pressure, are not reliable in the setting of RV dysfunction.14 Although useful for man-
aging other forms of pulmonary hypertension in the ICU, pulmonary artery (PA) cath-
eters are rarely used in the setting of PE.15 Data and experience interpreting PA
catheter numbers in acute PE are lacking and there is also concern of clot dislodge-
ment and accuracy of pressure measurements in the setting of nonuniform clot dis-
tribution in the vascular bed.
A few small nonrandomized studies suggest that, in intermediate-risk PE, treatment
with diuresis improved markers of RV strain as well as hemodynamics, whereas other
small studies suggest that volume expansion increases cardiac index.16–18 A prospec-
tive multicenter blinded randomized trial is currently ongoing to compare the effects of
diuresis and volume expansion in acute intermediate-risk PE.19 In the interim, the au-
thors favor judicious use of volume expansion to achieve euvolemia, while monitoring
for and avoiding other conditions that may excessively reduce RV preload, such as
pericardial effusions and cardiac arrhythmias.

EARLY PRIORITY FOR CLOT REDUCTION

Clot debulking treatment via systemic thrombolytics, endovascular procedures, sur-

gery, or otherwise must always be paramount in patients who are hypotensive from
PE. Clinicians should evaluate for systemic tissue plasminogen activator long before
considering whether to add dobutamine on top of norepinephrine or debating the
merits of an inhaled pulmonary vasodilator.
508 Zhao & Friedman

THE ROLE FOR VASOPRESSORS AND INOTROPES

Hemodynamics may need to be supported with vasopressors and sometimes ino-

tropes while waiting for definitive treatment to arrive, or during the time it takes for
definitive treatment to work. Occasionally vasoactive medications are needed for re-
sidual RV stunning even after clot debulking. Vasopressors are important to maintain
systemic perfusion as well as coronary perfusion to the pressure-overloaded RV. The
goal is to increase the ratio of systemic vascular resistance (SVR) to PVR. Inotropes
help to support RV contractility and, by virtue of this, LV filling. The key is to augment
cardiac output to a level commensurate with organ perfusion (Table 1).

MAINTAINING SYSTEMIC PRESSURE AND CORONARY PERFUSION: VASOPRESSORS

Norepinephrine is an alpha-adrenergic and beta-adrenergic agent that increases

systemic pressure with a modest effect on inotropy. The authors recommend norepi-
nephrine as the first-line agent for shock secondary to PE. Animal studies suggest
that norepinephrine improves cardiac output, vascular coupling, and shift tipping
point for RV collapse.20,21 Phenylephrine is another potent vasoconstrictor that
has been evaluated for right ventricular failure and can increase RV coronary perfu-
sion, but there is some concern that phenylephrine’s pure alpha-adrenergic effect
may decrease LV cardiac output.20,22 Both norepinephrine and phenylephrine
have a theoretic possibility of increasing PVR and pressure, but this rarely has prac-
tical clinical impact. Norepinephrine has a net benefit favoring an increase in SVR/
PVR.23 One study of patients with chronic pulmonary hypertension undergoing anes-
thesia suggested a superior hemodynamic response to norepinephrine versus

Table 1
Treatment of acute RV failure

Goals Treatment Comments

Preload optimization
Maintain systemic pressure
and coronary perfusion
Augment cardiac output
Pulmonary vasodilators
Judicious volume
expansion with
crystalloid
NE 1–40 mg/min is first line
Dobutamine 2–10 mg/kg/
min is first line
iNO 10–20 ppm or
aerosolized epoprostenol
0.03–0.05 mg/kg/min
 Avoid volume overload
 If CVP available and
increased, do not give
fluids; consider diuretics
Add vasopressin 0.04 U/min
when NE dose >15 mg/
min
 Add dobutamine only
after NE has already been
started
 Avoid milrinone because
of vasodilatory effects
 Epinephrine 1–10 mg/min
is second line
 Physiologic rationale
exists for pulmonary
vasodilators
 Evidence for benefit is
lacking but no indication
of harm
 Use inhaled pulmonary
vasodilators to avoid VQ
mismatch

Abbreviations: iNO, inhaled nitric oxide; NE, norepinephrine.

 Management of Right Ventricular Failure 509

phenylephrine.24 Vasopressin is a noncatecholamine vasoconstrictor that has a

theoretic advantage of increasing SVR without any increase on PVR.25 The authors
recommend its use as a second-line agent when norepinephrine doses exceed
15 mg/min, or if there is a subpar response to norepinephrine. Disadvantages of using
vasopressin as a first-line agent include lack of experience, minimal titratability, and
absence of inotropic properties.

MAINTAINING CARDIAC OUTPUT: INOTROPES

Inotropes can also improve hemodynamics in the setting of acute unstable PE. The au-
thors suggest the addition of inotropes if there is evidence of a low-cardiac-output state
that persists after blood pressure is stabilized with vasopressors. Epinephrine may be
useful because it has both vasoconstrictor and inotropic properties.26 Most clinical
experience is with the use of dobutamine. Doses are typically 3 to 5 mg/kg/min,
although, rarely, doses up to 10 mg/kg/min are necessary. Dobutamine has been shown
to decrease pulmonary arterial elastance and resistance, and to restore RV PA coupling
on pressure load–induced right ventricular failure.27 The authors recommend monitoring
metrics of end-organ perfusion such as urine output, mental status, and capillary refill,
as well as serial bedside echocardiograms for RV function and cardiac output to help
guide titration. Noninvasive cardiac output devices may also be helpful, but many are
not accurate in the setting of right ventricular failure. If a central line is in place, measure
and target a central venous saturation of 65% to 70% as a resuscitation end point
because it reflects oxygen supply and demand. A decrease in central venous saturation
reflects cardiac output if hemoglobin level and oxygen consumption are unchanged.
Dobutamine does have some vasodilatory properties and can cause hypotension if
used alone. However, the hypotensive effects are usually easily balanced out when it
is added on top of norepinephrine. In contrast, milrinone is often referred to as an ino-
dilator because of its potent blood pressure lowering effects. Animal models of PE sug-
gest that both dobutamine and milrinone may be effective in improving RV function.28
Some experts prefer milrinone because of a theoretically reduced risk for tachyarrhyth-
mias and a preferential effect on pulmonary vasodilation.2,29 However, the potential for
hypotension with milrinone is undesirable in the setting of high-risk PE. The authors
acknowledge the pulmonary vasodilatory properties of milrinone create a uniquely
important role in decompensated pulmonary hypertension but do not recommend its
use for acute shock from PE. Levosimendan, a calcium sensitizer that can improve
RV inotropy and PVR, is a lesser-known agent that shows some promise in preliminary
studies but is currently not approved for use in the United States.30 Dopamine exerts
various effects on cardiac output and vascular tone depending on doses delivered. It
has fallen out of favor because of unpredictability, increased arrhythmias, and the avail-
ability of superior alternative agents.31
When using inotropes, clinicians must monitor closely for arrhythmias because
they are both highly prevalent and devastating in patients with acute RV
dysfunction.32 Atrioventricular dissociation is poorly tolerated in acute right ventric-
ular failure. The failing RV becomes dependent on atrial contraction to maintain pre-
load.33 Sinus tachycardia can increase cardiac output and is beneficial to a point,
past which decreased filling time worsens RV and LV preload. Furthermore, exces-
sive tachycardia itself can increase RV myocardial work and further worsen supply-
demand mismatch. Digoxin is sometimes used in patients with chronic RV dysfunc-
tion from pulmonary hypertension because it increases inotropy without increasing
heart rate (and is useful for rate control), but it does not have a role in the acute right
ventricular failure setting, and has not been studied in the context of PE.34
510 Zhao & Friedman

MANAGING RIGHT VENTRICULAR AFTERLOAD: PULMONARY VASODILATORS

The authors emphasize that the most important method of reducing RV afterload in
unstable patients with acute PE involves rapidly reducing clot burden. In stable pa-
tients, heparin monotherapy is enough. Heparin alone was shown to reduce PVR by
16% after 24 hours in 1 study.35 This finding may be caused by heparin’s inhibitory ef-
fects on platelet aggregation, thus both facilitating clot dissolution and limiting the
release of vasoactive substances.36 In unstable patients, there has been interest in
supplementing treatment with pulmonary vasodilators because it is recognized that
the increase in PVR following PE is not simply caused by the thrombi themselves
but also by the resulting inflammatory and neurohormonal cascade.
Pulmonary vasodilators have long been used to treat pulmonary arterial hyperten-
sion. In 1 small randomized study, intravenous (IV) epoprostenol did not significantly
improve RV function when combined with usual care for acute PE.37 Although the
use of systemic parenteral therapy has traditionally been limited by concerns of sys-
temic hypotension, inhaled epoprostenol and nitric oxide (iNO) are agents with short
half-lives and limited systemic absorption, which makes them attractive targets for
use in acute PE.37,38 Inhaled pulmonary vasodilators are used commonly in unstable
patients with various forms of right ventricular failure in combination with increased
PVR. In addition to their effects on decreasing PVR, inhaled vasodilators may improve
oxygenation through optimization of ventilation/perfusion (V/Q) matching in the lungs.
Critically ill patients, including those with acute PE, have V/Q mismatch, so inhaled
pulmonary vasodilators are preferred to IV or oral agents. Recently, a randomized,
double-blind multicenter study compared administration of inhaled iNO with placebo
in patients with intermediate-risk PE.39 Although the study failed to show a significant
difference in the primary outcome (a composite of normal troponin level and RV by
echocardiographic criteria), there was a trend toward improvement in echocardio-
graphic parameters of RV dysfunction within 24 hours. There may remain a role for
iNO in acute PE, but more robust studies are needed to provide further clarity. For pa-
tients who survive the initial PE and subsequently develop chronic thromboembolic
pulmonary hypertension, riociguat is an oral pulmonary vasodilator that has been
shown to improve hemodynamics and patient symptoms.40

MANAGING RESPIRATORY FAILURE: INTUBATION AND MECHANICAL VENTILATION

Patients with PE may develop several indications for intubation and mechanical
ventilation. Severe hypoxemia may develop from V/Q mismatch, shunt, and
decreased mixed venous oxygen content.41,42 Contrary to many other groups of crit-
ically ill patients, those with acute PE should avoid endotracheal intubation and me-
chanical ventilation as much as possible because of the high risk of hemodynamic
collapse.43–45 Induction agents used to facilitate intubation may cause a decrease
in sympathetic tone and a significant decrease in systemic blood pressures,
reducing both RV perfusion and RV preload.46 In addition, they may also have a
direct negative inotropic effect on the myocardium, further decreasing cardiac
output. The transient period of apnea may lead to hypoxemia and hypercapnia,
both of which may cause an acute increase in PVR.47,48 Positive pressure ventilation,
particularly if tidal volumes are excessively high, may also increase PVR and worsen
RV dysfunction.49 If intubation is deemed necessary, the risk of cardiovascular
collapse may be reduced by ensuring close hemodynamic monitoring with vaso-
pressor agents readily available. Potent vasodilators/negative inotropes such as
propofol should be avoided, and the most hemodynamically neutral agent, such
as etomidate or ketamine, should be considered.50 One strategy that minimizes
 Management of Right Ventricular Failure 511

the adverse effects of induction agents/sedatives and maximizes the patient’s ability
to rely on physiologic respiratory mechanics to avoid periprocedural hypotension
and hypoxemia is awake fiberoptic intubation. In 1 small case series, patients with
acute right heart failure intubated using this strategy had 88% survival in the 24 hours
after intubation.51 When performing fiberoptic intubation in this population, adequate
topicalization with lidocaine should be emphasized to reduce abrupt shifts in sympa-
thetic tone from the procedure.52
Care should be taken to avoid lung overdistension both while bag masking the pa-
tient as well as after the patient is intubated. Notably, both low and high tidal volumes
may increase PVR, so avoidance of atelectasis and overdistension is necessary and a
lung-protective ventilation strategy similar to that used in acute respiratory distress
syndrome (ARDS) may be used.53 Similarly, higher positive end-expiratory pressure
(PEEP) levels may extrinsically compress pulmonary vasculature leading to increases
in PVR, whereas its role in alveolar recruitment and improvement of oxygenation may
reduce hypoxic vasoconstriction and PVR. No single PEEP strategy has been shown
to be preferential in this population, so tidal volumes and PEEP should be carefully
titrated for both gas exchange as well as hemodynamics. Prone positioning has
been shown to offload the RV in ARDS but that is thought to be related to improved
lung recruitment and gas exchange and is not recommended for right ventricular fail-
ure from acute PE54 (Table 2).

MANAGING RIGHT VENTRICULAR FAILURE WITH MECHANICAL SUPPORT:

EXTRACORPOREAL MEMBRANE OXYGENATION AND RIGHT VENTRICULAR ASSIST
DEVICE

In cases of severe shock or hypoxemia refractory to the therapies discussed earlier,

mechanical support may be used.10 This support may be in the form of extracorporeal
membrane oxygenation (ECMO) or right ventricular assist device (RVAD). Because cir-
culatory failure predominates over respiratory failure, venoarterial (VA) ECMO is

Table 2
Intubation and mechanical ventilation of patients with acute pulmonary embolism

Goals Treatment
Avoid intubation if  Treat the underlying cause (PE) first
possible  Respiratory failure should be considered an indication for
systemic thrombolytics or other advanced PE treatment
 Beware that intubation may precipitate cardiovascular
collapse
Cardiostable induction  Use medications with minimal vasodilatory properties
medications  Consider etomidate or ketamine
Maintain systemic blood  Consider starting norepinephrine before induction
pressure  Push-dose phenylephrine is useful
Maintain normoxia and  Hypoxia and hypercapnia lead to an increase in PVR
normocarbia  Attention to preinduction optimization
 Minimize apneic period (experienced provider intubates,
consider use of video laryngoscopy)
 Once intubated, adjust ventilator settings to achieve goals
Optimize tidal volumes  Tidal volumes too low or too high lead to an increase in PVR
 6–8 mL/kg IBW is a good starting point

Abbreviation: IBW, ideal body weight.

512 Zhao & Friedman

usually considered rather than venovenous ECMO. To date, there have been no pro-
spective studies assessing the role of ECMO in the setting of PE. In a retrospective
single-center series, early protocolized use of VA-ECMO resulted in 95% 90-day sur-
vival.55 Patients placed on ECMO were sometimes bridged to definitive therapy with
surgical embolectomy or catheter-directed lysis, but many were simply treated with
anticoagulation alone. Notably, patients in this series were evaluated for and placed
on ECMO early in their course, as opposed to a more traditional use of ECMO as
salvage therapy later on. A systematic review of case reports found an overall 70%
survival rate, with more than half of those patients receiving ECMO after cardiac ar-
rest.56 Another less invasive approach may be the use of a percutaneous
RVAD.57,58 One small series examined the use of the Impella RP (a percutaneous
microaxial pump that augments RV cardiac output) with catheter-directed thrombol-
ysis with good effect.59 Akin to ECMO, the goal of a temporary RVADs is to support
RV hemodynamics until the acute insult is addressed and PVR is reduced enough
to allow weaning and removal. Mechanical support modalities are discussed in greater
detail elsewhere in this issue.

SUMMARY

Acute right ventricular failure remains the leading cause of mortality associated with
acute PE. Although there is a lack of robust data to guide the management of this crit-
ically ill population, clinicians can apply their knowledge of the physiology of the RV
and the pathophysiology caused by a PE to tailor therapies toward each patient’s
needs. First, the clinician must decide on a strategy to debulk clot. The clinician should
carefully assess volume status and judiciously resuscitate, being mindful of the harms
in volume overloading the RV. Vasopressors are used to increase SVR/PVR, maintain
systemic blood pressure, and enhance coronary perfusion to the RV. Inotropes are
sometimes needed to maintain adequate cardiac output and LV filling, and improve
RV/PA coupling. Pulmonary vasodilators have a theoretic role, but evidence is lacking.
Avoid intubation and mechanical ventilation unless it is imperative, applying a
physiology-minded approach to both when performed. ECMO has an important role
in supporting cardiorespiratory failure from PE, and RVADs may have an expanding
role in the future.

DISCLOSURE

Dr O. Friedman is on the speaker’s bureau of Bristol Myers Squibb and Pfizer.

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